Polne razlike u imunskom odgovoru na vakcinu protiv gripa kod miševa različitih sojeva i uzrasta

Abstract

Biološki pol, genetska varijabilnost i starenje imaju uticaja na imunski odgovor, ali mehanizmi nisu sasvim razjašnjeni. Ciljevi disertacije su bili ispitivanje: 1) polnih razlika u imunskom odgovoru na vakcinu protiv gripa (inaktivisanu trovalentnu celovirusnu (CIV) i split (SV)) kod različitih sojeva miševa tokom starenja, određivanjem humoralnog odgovora na vakcinalne antigene i protektivnih potklasa IgG antitela; 2) ćelijskih i molekulskih mehanizama odgovornih za ove razlike određivanjem zastupljenosti: slezinskih folikulskih pomoćničkih T (Tfh) ćelija i folikulskih regulatornih T (Tfr) ćelija, B-ćelija germinativnog centra (GC B), citokinskog profila Th ćelija i proliferativne sposobnosti Th i B-ćelija. Rezultati ukazuju na intenzivniji humoralni imunski odgovor ženki Swiss miševa u odnosu na mužjake i intenzivniji odgovor na CIV u odnosu na SV. Sekrecija IgG2a je dominantna kod ženki imunizovanih CIV-om, a polne razlike se gube kod imunizovanih SV-om, što je povezano sa zastupljenošću Th1 i Th2 ćelija u slezini. Uticaj genetske varijabilnosti se ogleda u intenzivnijem odgovoru kod BALB/c u odnosu na C57BL/6 soj uz zadržane polne razlike i dominaciju IgG1 kod BALB/c miševa (izraženiji Th2 odgovor). Starenje utiče na smanjenje titra IgG antitela kod oba pola, i na odnos titra IgG2a(c)/IgG1 na sojno- i polno- specifičan način. Snažniji imunski odgovor se povezuje sa intenzivnijom proliferacijom Th i B splenocita u odgovoru na vakcinalne antigene, većim brojem Tfh i GC B splenocita i manjim brojem supresivnih Tfr splenocita (efikasnije je formiranje GC), većom zastupljenošću CD4+IL21+ ćelija. Rezultati ukazuju da pol, genetske karakteristike, uzrast, kao i tip vakcine mogu imati uticaj na imunski odgovor, što bi trebalo imati u vidu prilikom razvoja vakcine i strategije vakcinacije protiv gripa.

Biological sex, genetic variability, and aging influence the immune response, but the underlaying mechanisms are not fully elucidated. The aims of this dissertation were to investigate: 1) sex differences in the immune response to influenza vaccine (inactivated trivalent whole virus (WV) and split virus (SV)) in different mouse strains during aging, by determining the antibody response to vaccine antigens and protective IgG antibody subclasses; 2) cellular and molecular mechanisms underlying these differences by assessing the abundance of splenic follicular helper T (Tfh) cells, follicular regulatory T (Tfr) cells, germinal center B (GC B) cells, cytokine profile of Th cells, and proliferative capacity of Th and B cells. Results show a stronger humoral immune response in female Swiss mice compared to males and a stronger response to WV compared to SV. IgG2a secretion is dominant in females immunized with WV, while sex differences are lost in SV immunized mice, which is associated with the abundance of Th1 and Th2 cells in the spleen. Influence of genetic variability is reflected in a stronger response in BALB/c compared to C57BL/6 strain, with retained sex differences and dominance of IgG1 in BALB/c mice (indicating a more pronounced Th2 response). Aging leads to a decrease in IgG antibody titers in both sexes and affects the IgG2a(c)/IgG1 ratio in a strain- and sex-specific manner. A stronger immune response is associated with enhanced proliferation of Th and B splenocytes in response to vaccine antigens, increased numbers of Tfh and GC B splenocytes, and decreased numbers of suppressive Tfr splenocytes (facilitating GC formation), as well as increased abundance of CD4+IL21+ cells. These results indicate that sex, genetic characteristics, age, and vaccine type can influence the immune response, which should be considered in the development of influenza vaccines and vaccination strategies.